A functional model of sensemaking in a neurocognitive architecture.

Sensemaking is the active process of constructing a meaningful representation (i.e., making sense) of some complex aspect of the world. In relation to intelligence analysis, sensemaking is the act of finding and interpreting relevant facts amongst the sea of incoming reports, images, and intelligence. We present a cognitive model of core information-foraging and hypothesis-updating sensemaking processes applied to complex spatial probability estimation and decision-making tasks. While the model was developed in a hybrid symbolic-statistical cognitive architecture, its correspondence to neural frameworks in terms of both structure and mechanisms provided a direct bridge between rational and neural levels of description. Compared against data from two participant groups, the model correctly predicted both the presence and degree of four biases: confirmation, anchoring and adjustment, representativeness, and probability matching. It also favorably predicted human performance in generating probability distributions across categories, assigning resources based on these distributions, and selecting relevant features given a prior probability distribution. This model provides a constrained theoretical framework describing cognitive biases as arising from three interacting factors: the structure of the task environment, the mechanisms and limitations of the cognitive architecture, and the use of strategies to adapt to the dual constraints of cognition and the environment.

Defining the correctness of a diagnosis: differential judgments and expert knowledge.

Approaches that use a simulated patient case to study and assess diagnostic reasoning usually use the correct diagnosis of the case as a measure of success and as an anchor for other measures. Commonly, the correctness of a diagnosis is determined by the judgment of one or more experts. In this study, the consistency of experts' judgments of the correctness of a diagnosis, and the structure of knowledge supporting their judgments, were explored using a card sorting task. Seven expert pediatricians were asked to sort into piles the diagnoses proposed by 119 individuals who had worked through a simulated patient case of Haemophilus influenzae Type B (HIB) meningitis. The 119 individuals had varying experience levels. The expert pediatricians were asked to sort the proposed diagnoses by similarity of content, and then to order the piles based on correctness, relative to the known correct diagnosis (HIB meningitis). Finally, the experts were asked to judge which piles contained correct or incorrect diagnoses. We found that, contrary to previous studies, experts shared a common conceptual framework of the diagnostic domain being considered and were consistent in how they categorized the diagnoses. However, similar to previous studies, the experts differed greatly in their judgment of which diagnoses were correct. This study has important implications for understanding expert knowledge, for scoring performance on simulated or real patient cases, for providing feedback to learners in the clinical setting, and for establishing criteria that define what is correct in studies of diagnostic error and diagnostic reasoning.

Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion.

This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open-label, multiple-cohort, steady-state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty-nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809-1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.

The intramolecular asymmetric Pauson-Khand cyclization as a novel and general stereoselective route to benzindene prostacyclins: synthesis of UT-15 (treprostinil).

A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).